Slowly and passionately they catch up in the brain of people with Alzheimer's disease.
Abnormal bits of protein known as amyloid β glomerify each other to form the infamous plaques that reminded German psychiatrist Alois Alzheimer's of millet seeds when he first found them in a deceased patient's brain in 1906. And then there is rope the proteins, which usually help to stabilize the cell skeleton of brain cells, but can start to flame when people get older or when rope is defective.
The consequences are also well-known: Short-term memory loss usually comes first, so mood swings, language degradation, disorientation and confusion create inevitably. But how these symptoms are due to the two defective proteins and the spots and plaques they create have long been unclear.
To study Alzheimer's brain tissue, neurologists had to do with discs of brain that they could manipulate in the laboratory. But how comparable was this to what is happening in living, intact brains affected by Alzheimer's? About 15 years ago, the technology developed by neuroscientific Arthur Konnerth's laboratory at the Technical University of Munich offered a way to address this issue by allowing scientists to see the mouse's brains in action.
Marc Aurel Busche, a neuroscience and psychiatrist at the UK Dementia Research Institute in London, conducting research and counseling patients with memory problems, was the first to apply this new technique to mouse models of Alzheimer's. It has led to some surprising results, as outlined in an article by Konnerth, Busche and two other colleagues in Annual Review of Neuroscience . This interview has been edited for the length and clarity.
Can you explain basically how this technique allows us to see the brain in action?
What we really see is that calcium flows into the cells, which happens every time a nerve cell burns.
To make this visible, we add molecules to the brain cells that can bind calcium and will change their fluorescence when they do – a change we can see or detect using a microscope. For the studies we have done, we have removed a very small portion of the cortex, the outer layer of the brain, so we could also see other regions like the hippocampus, which is important in memory.
Recent developments now allow us to take pictures of the hippocampus without removing the cortex. But at least we have been able to show that the removal does not affect the mouse's behavior or level of activity.
Mice have quite different brains from ours and they do not live anywhere so long. How do you create a mouse model with a condition similar to Alzheimer's?
The development of mouse models is inspired by genetics. There are two types of Alzheimer's: a sporadic form that only occurs in the elderly, and a family-like form that sets in much earlier. In the second case, we often know exactly which genetic mutation causes it. We insert human genes with these mutations into the mouse DNA so that the mice overproduce, especially the protein from which amyloid β originates.
The engineered mice form amyloid plaques similar to humans, and they also have memory failure. But it is important to mention that these mice do not model all aspects of the disease. Many of them, for example, have Don't chew on ropes.
So they mimic Alzheimer's early approach rather than the one related to aging?
Yes, but in terms of the clinical symptoms and the way the brain tissue is affected by the disease, the two are not very different. So we think the mice are also useful in understanding the aging-related shape.
When you first used this new imaging technique to look at the brain activity of a mouse that overproduced human amyloid β, did you find what you expected?
no. Our hypothesis was that the brain cells around the amyloid plaques would be silent. But we found the opposite – many of these neurons were hyperactive. In the hippocampus, a crucial area for memory consolidation, this hyperactivity occurred even before the formation of amyloid plaques.
This suggests that the hyperactivity is not due to the plaques themselves, but to amyloid proteins in solution: Amyloid plaques tend to be surrounded by a halo of soluble amyloid β. The Hassocampus was subsequently also found to be hyperactive in people with very early Alzheimer's.
Could this hyperactivity be a test in healthy cells in the hippocampus to compensate for other cells that may have been damaged by the disease already?
It was the first hypothesis that many people had that the hippocampus should work a little harder to maintain its memory function. However, there is growing evidence that this may not be true. In human studies, cognitive decline is faster in people who have the highest levels of hyperactivity. This is the opposite of what you would expect if a more active hippocampus helps them compensate for the damage. And in mice, it has been shown repeatedly that hyperactive neurons are actually harmful to normal function.
Can we say it rather than work harder, they just make more noise?
Yes. If some cells are active all the time, they can drown out the meaningful signals from others.
Can this hyperactivity explain some of the symptoms seen in the early stages of Alzheimer's?
A certain degree of coherent activation of the hippocampus and cortex is important for the successful storage and retrieval of memory. Hyperactivity affects this communication, and mice with a hyperactive hippocampus are impaired in cognitive and behavioral tests. When we treat them to reduce hyperactivity, communication is normalized and their behavior improved.
Hyperactivity can also interfere with activity and coordination of brain areas in the so-called "standard fashion network" – a series of interconnected brain areas that are active when we do not perform a task when our minds are left to wander. This network plays an important role, for example in the formation of memories of oneself, when and where you had lunch yesterday – known as self-reflecting memories.
I think it's important to mention that apart from memory failure, many people with Alzheimer's also experience depression, attention deficit or sleeping problems early – symptoms we didn't use to pay close attention to. It is not clear whether these are all manifestations of the disease or early risk factors for developing it, but some of these may also concern changes in the standard mode network. Depression, for example, is affected by the same circuit; It has many self-reflecting aspects.
The connection with sleeping problems is interesting and worrying. What is known about it?
I began to look at sleep in mice after noting that my patients in the memory clinic often complain of sleep disorders. Looking at the electrical activity of human or mouse brain using EEG [electroencephalography, a recording of electrical activity in the brain]we can see separate slow waves traveling across the brain during the deeper stages of sleep. It turns out that these waves are less coherent and therefore quite likely impaired in Alzheimer's.
Sleeping can be an important driver of Alzheimer's progression, as we now know it is affected very early. Many studies show that the proteins we believe run the disease, released in greater amounts when we are awake, and that sleep can help remove them. In that sense, sleep hygiene – minimizing the impact of factors such as activities or drinks that can interfere with your sleep – is important. But again we do not know for sure that insomnia contributes directly to the development of Alzheimer's. It may also be that sleep disorders are only an early symptom of the disorder.
Can sleeping pills be part of the solution?  The problem with sleeping pills is that they often suppress the normal rhythm of sleep. Most of the drugs we typically use change normal sleep physiology – some of them are more like anesthesia.
It is not the normal form of sleep that is healthy for you. They can provide great relief in a short period of time if someone really does not sleep, but it is not a permanent solution.
Have the hyperactivity findings inspired new pharmacological approaches to Alzheimer's?
] We believe that hyperactivity can also contribute to the epilepsy-like or epileptic activity first described in mice overproducing human amyloid β at the laboratory of Lennart Mucke at UC San Francisco. Many clinicians were initially skeptical, but it turns out that such activity occurs in 15 percent to 25 percent of Alzheimer's patients. Now, there are experiments with the epilepsy drug levetiracetam, which has been shown to reduce epileptiform activity in the amyloid-β mouse model while improving their cognition. It is being tested in a large phase III clinical trial to see if it can help in early Alzheimer's.
A few other medical trials on Alzheimer's attempt to prevent the formation or reduce the concentration of amyloid-β have been completed early What could they have missed?
First of all, there are still amyloid targeting treatments in Phase III trials, and I really hope some of them may prove positive. But I think the latest setbacks indicate that the mice we use are incomplete models and that the other protein, rope, can make the difference. Many groups have shown that we can substantially cure these amyloid-producing mice. But it is not effective in patients because they also have the tau protein. The current thinking in the field, which is reflected in the design of the clinical trials, is that there is no particular interaction between amyloid-p and rope. But research over the last few years, including our own, shows that there is a synergy between the two proteins and that amyloid β can make the effects of rope worse.
In your recent study, you have tried to shed some light on the way the two proteins interact. It shows that when neurons in the brain of mice are designed to overproduce human tau as well as amyloid β, they are not hyperactive as they are in amyloid-only mice but silent. It seems quite contradictory – how can these results be united?
I think it is really important to look at how the disease develops in space and time. It is undeniable that about one-fifth of the patients have epileptiform activity early on – that the hippocampus is hyperactive in many patients with early Alzheimer's – and that when interacting with the outside world, their standard mode often does not turn off the way it normally would. So there are plenty of signs of increased activity.
At the same time, we have known for some time that the brain is silent later in the course of the disease – studies show a decrease in metabolism and blood flow.  We have a simple model right now that is based on what we see in the patients brain. Amyloid plaques occur first, and as long as we mostly have amyloid β, we expect to see more hyperactivity. So when rope starts to spread, it will eventually become dominant, and more and more nerve cells will become silent. This volume can be reversible – in the mice, these cells are at least not dead, but in a resting state. However, to prevent or even repair this situation, I think we will very likely have to target both proteins at the same time.